Abstract 3744: Targeted therapy for breast cancer bone metastases using mRNA engineered mesenchymal stem cells

Abstract

Abstract Bone is a primary metastatic site in breast cancer, and bone metastases are associated with poor survival and a dramatic decrease of patient's quality of life. Current treatments lack specificity for bone metastatic niches, leading to poor drug delivery and systemic toxicity. Mesenchymal stem/stromal cells (MSCs) represent ideal trophic vehicles for drug delivery to bone metastases as they are readily available, easy to expand, and display a natural, although inefficient, homing to bone and tumor sites. This work aimed to develop MSCs that are engineered through simple mRNA transfection with both bone vasculature-homing ligands and therapeutics to improve targeted delivery and efficacy. The transfection of protein-coding mRNA is an effective tool to engineer simultaneously and transiently cells with multiple factors to control the fate of transplanted cells, while mitigating risks associated with viral-based engineering. Human bone marrow-derived MSCs from healthy donors were engineered with synthetic mRNA to express homing ligands P-selectin glycoprotein ligand-1 (PSGL-1)/Sialyl Lewis X (sLeX), and anti-tumor agents cytosine deaminase (CD) and osteoprotegerin (OPG). PSGL-1/sLeX allow MSCs to efficiently target bone tumor vasculatures that overexpress P- and E-selectins. CD is a convertase that locally converts inactive pro-drug 5-Fluorocytosine (5-FC) to active drug 5-Fluorouracil. OPG is a natural decoy receptor for one of the main bone resorptive factors expressed in bone metastases, RANKL (Receptor activator of nuclear factor kappa-B ligand), and thus blocks the vicious cycle existing between tumor growth and bone resorption. First, we demonstrated that MSCs could be efficiently engineered through mRNA transfection to express simultaneously homing ligands PSGL-1 and sLeX, CD and OPG. We evaluated improved cell homing and anti-tumor functions of engineered stem cells in vitro. Expression of PSGL-1 and sLeX increased MSC rolling and tethering on an activated endothelium under shear flow condition. When co-cultured with human breast cancer cells MDA-MB231 in presence of 5-FC, engineered MSCs induced both breast cancer and MSC death within 5 days. Finally, secreted OPG is able to prevent osteoclastogenesis in vitro using murine osteoclast precursors. We are currently evaluating biodistribution, homing to bone metastatic niches and anti-tumor efficacy of engineered MSCs in vivo using establish models of breast cancer bone metastases (intratibial and intracardiac injection of MDA-MB-231 cells). As bone metastases are osteolytic lesions, bone remodeling will also be measured using histomorphometry. To conclude, our engineered MSCs can potentially be safer vectors to effectively target and treat bone metastases, thus decreasing off-target systemic toxicity. This next-generation of engineered MSCs has the potential to address an unmet challenge for bone metastases treatment. Citation Format: Aude Segaliny, Jason Cheng, Weian Zhao. Targeted therapy for breast cancer bone metastases using mRNA engineered mesenchymal stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3744.